A Phase I, Open Label Study of AT-101 Plus Radiotherapy and Temozolomide and of AT-101 Plus Adjuvant Temozolomide for Patients With Newly-Diagnosed Glioblastoma Multiforme
18 Years
N/A
Both
Brain and Central Nervous System Tumors
Trial Information
A Phase I, Open Label Study of AT-101 Plus Radiotherapy and Temozolomide and of AT-101 Plus Adjuvant Temozolomide for Patients With Newly-Diagnosed Glioblastoma Multiforme
OBJECTIVES:
Primary
- Determine the maximum tolerated dose (MTD) of gossypol (AT-101) when administered with
radiotherapy (RT) and concurrent temozolomide (TMZ) in patients with newly diagnosed
glioblastoma multiforme.
- Determine the MTD of gossypol when administered with adjuvant TMZ after standard RT and
concurrent TMZ in these patients.
Secondary
- Assess the toxicity of these treatment regimens.
- Assess and describe the pharmacokinetics of gossypol.
- Determine, preliminarily, the therapeutic activities of these regimens.
- Determine the relationship between these regimens and cellular and molecular features
identified in tumor biopsy specimens.
OUTLINE: This is a multicenter, open-label, nonrandomized, dose-escalation study of
gossypol. Patients are assigned to 1 of 2 treatment groups. Patients who participate in
group I are NOT eligible for group II.
- Group I: Patients receive oral gossypol and undergo radiotherapy once daily 5 days a
week for up to 6 weeks. Patients also receive oral temozolomide once daily for up to 6
weeks. Treatment continues in the absence of disease progression or unacceptable
toxicity.
- Group II: Patients receive oral temozolomide on days 1-5 and oral gossypol once daily
on days 1-21. Treatment repeats every 28 days for up to 6 courses in the absence of
disease progression or unacceptable toxicity.
Cohorts of 3-10 patients per treatment group receive escalating doses of gossypol until the
maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which 2 of 6
or 3 of 10 patients experience dose-limiting toxicity.
Patients undergo blood collection periodically for pharmacokinetic studies. Tumor tissue
samples are examined for biomarkers including, but not limited to, Bcl-2 family protein
expression (e.g., Bcl-2, Bcl-xL, MCl-1, Bax, Bak, and BH3 domain), MGMT gene methylation
status, and gene expression array.
After completion of study treatment, patients are followed every 2 months.
PROJECTED ACCRUAL: A total of 50 patients will be accrued for this study.
Inclusion Criteria
DISEASE CHARACTERISTICS:
- Histologically confirmed supratentorial grade IV astrocytoma (glioblastoma
multiforme)
- Meets 1 of the following criteria:
- Completed surgery within the past 6 weeks (group I)
- Received radiotherapy and concomitant temozolomide at least 4 weeks but no more
than 7 weeks prior to start of study treatment (group II)
- Must be on a stable corticosteroid regimen (no increase for 5 days)
PATIENT CHARACTERISTICS:
- Karnofsky performance status 60-100%
- Hemoglobin ≥ 10 g/dL
- Absolute neutrophil count ≥ 1,500/mm³
- Platelet count ≥ 100,000/mm³
- Creatinine ≤1.5 mg/dL
- Bilirubin ≤ 1.5 mg/dL
- ALT and AST ≤ 2.5 times upper limit of normal
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception during and for 2 months after
completion of study treatment
- Mini Mental State Exam score ≥ 15
- Must be able to swallow and retain oral medication
- No serious concurrent infection or medical illness that would preclude study
participation
- No other malignancy within the past 5 years, except for curatively treated carcinoma
in situ or basal cell carcinoma of the skin
- No sensory neuropathy ≥ grade 2
- No allergies to gossypol
- No symptomatic hypercalcemia or hypercalcemia > grade 2
- No gastrointestinal disease including any of the following:
- Malabsorption syndrome
- Disease significantly affecting gastrointestinal function
- Ulcerative colitis
- Inflammatory bowel disease
- Partial or complete small bowel obstruction
PRIOR CONCURRENT THERAPY:
- See Disease Characteristics
- Recovered from the immediate postoperative period
- No prior radiotherapy, chemotherapy, immunotherapy, therapy with biologic agents
(including immunotoxins, immunoconjugates, antisense agents, peptide-receptor
antagonists, interferons, interleukins, tumor-infiltrating lymphocyte therapy,
lymphokine-activated killer cells or gene therapy), or hormonal therapy for this
brain tumor (group I)
- Prior glucocorticoid therapy allowed
- No prior polifeprosan 20 with carmustine implant (Gliadel wafers) (group I)
- No prior gossypol
- No prior radiosurgery or brachytherapy
- No prior resection of the stomach or small intestine
- No other concurrent anticancer therapy (i.e., chemotherapeutics or investigational
agents)
- No concurrent cytochrome p450 enzyme-inducing anticonvulsant drugs
- No concurrent prophylactic filgrastim (G-CSF)
- No concurrent iron supplements
- Nutritional supplements containing iron allowed
- No concurrent intensity-modulated radiotherapy
- No concurrent electron, particle, implant, or stereotactic radiosurgery boost
Type of Study:
Interventional
Study Design:
Allocation: Non-Randomized, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Maximum tolerated dose
Safety Issue:
Yes
Principal Investigator
John Fiveash, MD
Investigator Role:
Study Chair
Investigator Affiliation:
University of Alabama at Birmingham
Authority:
United States: Food and Drug Administration
Study ID:
NABTT-0602 CDR0000507451
NCT ID:
NCT00390403
Start Date:
February 2007
Completion Date:
Related Keywords:
- Brain and Central Nervous System Tumors
- adult glioblastoma
- adult gliosarcoma
- adult giant cell glioblastoma
- Glioblastoma
- Nervous System Neoplasms
- Central Nervous System Neoplasms
Name | Location |
|---|---|
| Abramson Cancer Center of the University of Pennsylvania | Philadelphia, Pennsylvania 19104-4283 |
| Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Baltimore, Maryland 21231-2410 |
| Cleveland Clinic Taussig Cancer Center | Cleveland, Ohio 44195 |
| Josephine Ford Cancer Center at Henry Ford Hospital | Detroit, Michigan 48202 |
| Winship Cancer Institute of Emory University | Atlanta, Georgia 30322 |
| Wake Forest University Comprehensive Cancer Center | Winston-Salem, North Carolina 27157-1096 |
| H. Lee Moffitt Cancer Center and Research Institute at University of South Florida | Tampa, Florida 33612 |
| Lurleen Wallace Comprehensive Cancer at University of Alabama - Birmingham | Birmingham, Alabama 35294 |
